Method of relieving symptoms of gastroesophageal reflux disease

ABSTRACT

The invention relates to a method for relieving or ameliorating symptoms of gastroesophageal reflux disease by administering a medicament that includes the cholecystokin-2 (CCK-2) receptor antagonist itriglumide and a proton pump inhibitor (PPI).

FIELD OF THE INVENTION

The present invention relates to the combination of thecholecystokinin-2 (CCK-2) receptor antagonist Itriglumide and protonpump inhibitors (PPI) for the treatment of patients suffering fromgastrointestinal or related disorders.

BACKGROUND OF THE INVENTION

Physicians have long recognised that conditions affecting the uppergastrointestinal (GI) tract commonly produce upper abdominal pain,discomfort, abdominal fullness, bloating, early satiety, nausea,vomiting, belching, heartburn and regurgitation. Such symptoms aretypically postprandial and occur either alone or in combination.Overall, upper GI symptoms, including both dyspeptic-type andreflux-type, affect more than 25% of adults in the Western world andhave a significant, negative impact on both functional status and senseof individual well-being (Tougas et al., Am J Gastroenterol. 1999; 94:2845-2854). Symptoms related to disorders of upper gut function areamong the most common presenting complaints in primary-care and GIspecialty medical practice. These disorders commonly include, but arenot limited to, GERD (gastroesophageal reflux disease), GERD witherosion, NERD (non-erosive reflux disease), NUD (non-ulcer dyspepsia),PUD (peptic ulcer disease), FD (functional dyspepsia), diabeticgastroparesis, gastrointestinal ulcers, Zollinger-Ellison syndrome, andantral G-cell hyperplasia.

Upper GI disorders are typically classified by anatomic region, e.g.,those of esophageal origin and those of gastroduodenal origin, based onepidemiological evidence pointing to the existence of site-specificclusters of symptoms. However, the GI tract's anatomic continuity andintegrated function in digestion and absorption of nutrients makes theseparation of symptom clusters by site somewhat artificial. In fact,considering the diaphragm to be an anatomic boundary for defining upperGI disorders, e.g., attributing symptoms localised above the diaphragmsuch as heartburn to the esophagus, a thoracic organ, and symptomslocalised below the diaphragm such as epigastric pain and discomfort tothe stomach, an abdominal organ, has not been a very useful construct.For example, “heartburn” as the sole or predominant symptom to definegastroesophageal reflux disease (GERD) has very low sensitivity (38%)albeit high specificity (about 90%) (Dent et al., Gut. 2004, 53 (May):Supp 4:1-24). Rather than occurring alone as a manifestation of GERD,heartburn is associated with epigastric pain in at least two thirds ofpatients. Equally disturbing from the vantage point of defining upper GIdisorders by location of symptoms, is the situation for dyspepsia. In aDanish study, 500 patients with dyspeptic symptoms (pain or discomfortin the epigastrium with or without heartburn, regurgitation, nausea,vomiting or bloating) were referred by their general practitioners forenrolment in a study comparing treatment strategies (H. pylori test—anderadicate versus prompt endoscopy) (Lassen et al, Lancet 2000,356:455-460). Although the main entry criterion was epigastric pain ordiscomfort, which was reported by all patients, 32% had heartburn and/orregurgitation as their dominant symptom, which was almost as manypatients as had dominant epigastric pain (37%). (See Lassen et al)Therefore, the available data indicate that significant overlap ofsymptoms exists in esophageal and gastric disorders; GERD patients havedyspeptic symptoms and dyspeptic patients have heartburn and/orregurgitation.

Given on the one hand the above described overlap of symptoms inpatients with upper GI disorders and on the other hand the multiplicityof the underlying mechanisms of upper GI disorders, it is very unlikelythat a pharmacological intervention directed versus a single chemicalclass represents an effective strategy for treating any upper GIdisorders.

As the goal for the management of patients with upper GI disorders isaimed to provide symptom relief, improved quality of life and healing ofany macroscopical lesion, if present, dyspeptic symptoms associated withupper GI disorders, therefore, represent an area of unmet need becausethere is no approved treatment for dyspeptic symptoms in patients. Inaddition, while there is compelling evidence for the effectiveness ofacid suppression therapy in patients with symptomatic heartburn and/orregurgitation due to GERD, there is lack of convincing evidence ofeffectiveness of acid suppression therapy for dyspeptic symptomsassociated with GERD. Indeed, it is a frequent observation that themajority of patients treated with a PPI for GERD symptoms are left withresidual dyspeptic symptoms and treatment with standard PPI therapy fordyspeptic symptoms rarely show more than 10% efficacy advantage of PPIover placebo.

In addition, there are still some areas that can be identified wheretreatment of patients with GERD could be further refined or enhanced(Vakil N. Aliment Pharmacol Ther 2004; 19: 1041-1049), which include:lack of complete symptom control, as 75% of patients continued toexperience heartburn frequently (Crawley J A, Schmitt C M. J ClinOutcomes Management 2000; 7: 29-34); variability in the inhibition ofgastric acid secretion (Chiverton S G. Aliment Pharmacol Ther 1992; 6:103-111); effective 24-h control of intragastric pH (Hatelbakk J G etal. Aliment Pharmacol Ther 1998; 12: 1235-1240; Katz P O et al. AlimentPharmacol Ther 2000; 14: 709-714); onset of action, as all currentlyavailable PPS may take 3-5 days to achieve maximal acid inhibition attherapeutic doses (Tytgat G N. Eur J Gastroenterol Hepatol 2001; 13(Suppl. 1): S29-33).

In particular, the slow onset of action is an intrinsic limitation ofall exiting PPIs used a monotherapy in GERD as it is strictly linked tothe pharmacokinetics and mode of action of all PPIs. After absorptionand distribution PPIs given their pK_(a) accumulate in the acid space ofthe canaliculus of secreting parietal cell where they are transformedinto the active sulphenamide which forms non-competitive, covalent andirreversible bonds with the key cysteines of the H⁺, K⁺-APTase (Sachs Get al. Annu Rev Pharmacol Toxicol 1995; 35: 277-305). Due to theirreversible nature of this binding, a steady-state inhibition isachieved only after 3 or 4 days of treatment. This can be attributed totheir very short half-life in combination with an activation of over 75%of the pumps and constant pump turnover in the face of covalentinhibition of the pump (Sachs G. Eur J Gastroenterol Hepatol. 2001; 13(Suppl. 1): S35-S41).

Different strategies might be used to overcome the slow onset of actionof all existing PPIs and possibly the scarce effect on dyspepticsymptoms.

For example new drugs are being developed such as the new class ofPotassium-competitive acid blockers (P-CABs) which might offer a fasteronset of action as these drugs bind ionically to the proton pump at ornear the potassium-binding site in a K⁺-competitive manner, therebyblocking acid secretion through a direct, reversible mechanism (Pope AJ, Sachs G. Best Pract Res Clin Gastroenterol 2002; 16: 835-849; WurtsW, Hartmann M. Yale J Biol Med 1996; 69: 233-243).

An alternative approach might be represented by the combination of aPPIs to an anti-secretive drug acting with a different mechanism ofaction for example at receptors involved in the regulation of gastricacid secretion, like H₂ or CCK-2 (formerly “gastrin”) receptorantagonist. These antagonists although not as efficacious as PPIs ininhibiting gastric acid secretion, act faster than PPIs as they arereversible antagonists, and therefore might be used in combination withPPIs to reach the goal of quickly achieving and then maintainingadequate inhibition of gastric acid secretion, thus with a faster andmore complete symptom relief.

Of particular interest is the combination of PPIs with CCK-2 receptorantagonists which might offer a unique advantage among allanti-secretive drugs as, due to their mode of action, in addition to theantisecretive properties, they are also able to counteract theunavoidable consequences of the hypergastrinemia which inevitablyaccompanies the reduction of intragastric acid secretion, regardless ofthe means used to achieve it, as the reduced acidity inevitably leads tothe increased release of gastrin by antral G cells (Maton P N. N Engl JMed 1991; 324: 965-975). In addition, CCK 2 receptor antagonists mightbe able to block other effects of cholecystokinin (CCK) and/or gastrin(see below).

CCK belongs to the group of substances known as brain-gut peptides andfunction as a neuropeptide and as a gut hormone. (Noble et al.,Pharmacol. Rev. 1999, 51(4):745-781; Crawley et al., Peptides 1994,15(4):731-755). It is now evident that at least two different receptors,namely CCK-1 (formerly CCKA or alimentary) and CCK-2 (formerly CCKB orbrain) receptors, mediate CCK biological actions. (Noble et al.,Pharmacol. Rev., 1999, 51(4):745-781; Woodruff and Hughes, Ann. Rev.Pharmacol. 1991, 31:469-501).

CCK is secreted primarily in response to meals and plays awell-recognised role in regulating gallbladder contraction andpancreatic enzyme secretion. Over the last decade, considerable evidencehas emerged to support the concept that CCK plays an equally importantrole in the regulation of motor and sensory functions at various levelsof the human upper GI tract. Specifically, the native peptide delaysgastric emptying, modulates gastric sensory function (especially inresponse to fat), increases the rate of meal-induced, transient loweresophageal sphincter relaxations (TLESRs) and affects small bowel andcolonic transit.

Gastrin is closely related to CCK and is secreted by G cells located inthe gastric antral mucosa and upper small intestine. Gastrin exertsthree main gastrointestinal effects: stimulation of acid secretiondirectly from parietal cells; stimulation of acid production viaincreased histamine release from enterochromaffin like (ECL) cells andstimulation of somatostatin release (Schubert et al., Yale J. Biol. Med1992; 65: 553-60). Furthermore, gastrin has a trophic effect on thegastric mucosa and stimulates the growth of gastrin-sensitive malignantcells (Rehfeld et al., Adv. Cancer Res. 1994, 63: 295-347).

CCK/gastrin receptors have been classified based on their anatomicallocation. The CCK₁-subtype has been found in the gallbladder, pancreasand intestine. The CCK₂-subtype has been found in discrete regions ofthe brain such as the cerebral cortex, hippocampus, nucleus accumbens,caudate-putamen and thalamus. Extensive evidence now indicates that CCK₁receptors are also present in the brain and conversely that CCK₂receptors are also present in the periphery, principally in the stomach.Furthermore, both receptors are expressed on human lower esophagealsphincter (LOS) (Gonzales et al., Neurogastroenterol. Mot. 2000; 12,539-546).

Gastrin is released in response to food or in response to theneutralisation of stomach pH (Walsh, Gastrointestinal Hormones inPhysiology of the Gastrointestinal Tract. Johnos L. R. (Ed.), RavenPress: New York. 1987, 181-259). The increase of circulating gastrinplasma levels stimulates the proliferation of the oxyntic mucosal cells,in particular the parietal and ECL cells (Enochs et al., Am. J. Physiol.1977, 223: E223).

Elevated fasted and postprandial gastrin levels have been described inseveral diseases such as peptic ulcer, Zoelliger-Ellison syndrome,gastrinomas, and G-cells hyperplasia (Modlin et al, Gastroenterology1996, 111:783-810). Moreover chronic infection with Helicobacter pyloriis associated with increased basal and gastrin stimulated gastric acidsecretion (McGowan et al., Gastroenterology 1996, 110: 926-938).

Therefore, CCK2 receptor antagonists may have a therapeutic potentialsas antisecretory drugs, in peptic ulcer disease as well as in all thosepathological conditions characterised by an hypertrophy of the gastricmucosa.

Itriglumide (Code Number CR 2945), (R)-1-napthalenepropanoicacid-β[2[(2-(8-azaspiro[4.5.]dec-8-ylcarbonyl)4,6-dimethyl-phenyl]amino]-2-oxoethyl]is a novel, non peptide CCK₂ receptor antagonist developed byRottapharm, formerly Rotta Research Laboratorium. The pharmacologicalprofile of the compound is characterised by a high potency, selectivityand favourable toxicological profile (Makovec et al., Eur. J.Pharmacol., 1999, 369: 81-90).

Yet, the combination of a PPI and Itriglumide has not been described fora treatment of gastrointestinal disorders, even if some pharmaceuticalcompositions comprising CCK-B antagonists and a proton pump inhibitorsto control gastric acid secretion in gastrointestinal disorders havebeen described in the literature. (See WO04/098610, WO04/101533,WO04/098609, WO03/041714, WO01/90078, WO01/85724, WO01/85723,WO01/85704, WO01/85167, and WO93/12817).

SUMMARY OF THE INVENTION

The subject matter of the invention is defined by the appended claims.

In one embodiment, the invention relates to treating gastrointestinaldisorders by administering to a patient a first amount of Itriglumideand a second amount of a proton pump inhibitor (PPI). The subjects beingtreated are suffering from GERD (Gastroesophageal Reflux Disease), GERDwith erosion, NERD (Non-Erosive Reflux Disease), NUD (Non-UlcerDyspepsia), PUD (Peptic Ulcer Disease), FD (Functional Dyspepsia),Diabetic Gastroparesis, Nocturnal heartburn, Heartburn, Bloating,gastrointestinal ulcers, Zollinger-Ellison syndrome and antral G-cellhyperplasia.

In another embodiment, the invention relates to a pharmaceuticalcomposition for treatment of gastrointestinal disorders comprising (i)Itriglumide, (ii) a proton pump inhibitor (PPI) and (iii) apharmaceutically acceptable carrier or excipient, wherein Itriglumideand PPI are present at therapeutically effective dosages to providerapid and sustained relief effect.

DETAILED DESCRIPTION OF THE INVENTION

As specified above, the instant invention provides a novel drugcombination of Itriglumide and a proton pump inhibitor for the treatmentand prevention of gastrointestinal and other disorders. Preferably, theCCK-2 receptor antagonist Itriglumide and the proton pump inhibitor areadministered at therapeutically effective dosages which, when combined,provide a rapid and sustained beneficial effect.

Definitions

Itriglumide can form salts and solvates which are also within the scopeof this invention. Reference to Itriglumide is understood to includealso its racemate mixture as well as salts and solvates thereof, unlessotherwise indicated.

The term “combination” applied to active ingredients is used herein todefine a single pharmaceutical composition (formulation) comprising bothdrugs of the invention (i.e., the CCK-2 receptor antagonist Itriglumideand a proton pump inhibitor) or two separate pharmaceutical compositions(formulations), each comprising a single drug of the invention (i.e.,the CCK-2 receptor antagonist Itriglumide or a proton pump inhibitor),to be administered conjointly.

Within the meaning of the present invention, the term “conjointadministration” is used to refer to administration of the CCK-2 receptorantagonist Itriglumide and proton pump inhibitor simultaneously in onecomposition, or simultaneously in different compositions, orsequentially. For the sequential administration to be considered“conjoint”, however, Itriglumide and proton pump inhibitor must beadministered separated by a time interval that still permits to obtainrapid onset of action as well as good long-term efficacy for thetreatment of gastrointestinal and related disorders. For example, theCCK-2 receptor antagonist and proton pump inhibitor must be administeredon the same day (e.g., each—once or twice daily), preferably within anhour of each other, and most preferably simultaneously.

The term “treating” is used herein to mean to relieve, alleviate, delayor prevent at least one symptom of a disease in a subject. For example,in relation to a gastrointestinal disorder, the term “treat” may mean torelieve or alleviate at least one symptom selected from the groupconsisting of increased tension of the wall of a viscous, increasedintravisceral pressure, cramps, colitis, gnawing, abdominal pain,constipation, diarrhoea, nausea, vomiting, urge to defecate, tenesmus,hematochezia, etc. Within the meaning of the present invention, the term“treat” also denote to arrest, delay the onset (i.e., the period priorto clinical manifestation of a disease) and/or reduce the risk ofdeveloping or worsening a disease.

For example, as disclosed herein, a prophylactic administration ofItriglumide in combination with a proton pump inhibitor can protect arecipient subject at risk of developing a gastrointestinal disorder.Similarly, according to the present invention, a therapeuticadministration of Itriglumide conjointly with a proton pump inhibitorcan lead to slow-down in the development of clinical symptoms or evenregression of symptoms.

Within the meaning of the present invention, the term “proton pumpinhibitor” is used to refer to compounds that can suppress the functionof the hydrogen-potassium adenosine triphosphatase enzyme system toreduce the release of acid in the stomach and intestines. The mostcommonly known proton pump inhibitors include but are not limited toOmeprazole, Lansoprazole, Esomeprazole, Pantoprazole and Rabeprazole.

The CCK-2 receptor antagonist of the present invention is Itriglumide,Code Number CR 2945, namely (R)-1-napthalene-propanoicacid-β[2-[2-(8-azaspiro[4.5.]dec-8-ylcarbonyl)4,6-dimethylphenyl]amino]-2-oxoethyl].This compound, its racemate and methods for their preparation aredisclosed in WO98/00404 and WO97/02248, respectively.

Various salts and isomers (enantiomers) of Itriglumide can be used. Thenature of the salt or isomer is not critical, provided that it isnon-toxic and does not substantially interfere with the desiredpharmacological activity.

The term “salts” includes salts of free bases.

Pharmaceutically acceptable base addition salts are formed with metalsor amines, such as alkali and alkaline earth metals or organic amines.Examples of metals used as cations are sodium, potassium, magnesium,calcium, and the like. Examples of suitable amines areN,N′-dibenzylethylenediamine, choline, diethanolamine,dicyclohexylamine, ethylenediamine and N-me-thylglucamine.

As used herein the term “therapeutically effective” applied to dose oramount refers to that quantity of a compound or pharmaceuticalcomposition that is sufficient to result in a desired activity uponadministration to a mammal in need thereof. More specifically, the term“therapeutically effective”refers to that quantity of a compound orpharmaceutical composition that is sufficient to reduce or eliminate atleast one symptom of a gastrointestinal disorder.

The phrase “pharmaceutically acceptable”, as used in connection withcompositions of the invention, refers to molecular entities and otheringredients of such compositions that are physiologically tolerable anddo not typically produce untoward reactions when administered to amammal (e.g., a human). Preferably, as used herein, the term“pharmaceutically acceptable”means approved by a regulatory agency ofthe Federal or a state government or listed in the U.S. Pharmacopoeia orother generally recognised pharmacopoeia for use in mammals, and moreparticularly in humans.

The term “carrier” applied to pharmaceutical compositions of theinvention refers to a diluent, excipient, or vehicle with which anactive compound (e.g., an and/or) is administered. Such pharmaceuticalcarriers can be sterile liquids, such as water, saline solutions,aqueous dextrose solutions, aqueous glycerol solutions, and oils,including those of petroleum, animal, vegetable or synthetic origin,such as peanut oil, soybean oil, mineral oil, sesame oil and the like.Suitable pharmaceutical excipients also include binding agents (e.g.,pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol,sorbitol and other reducing and non-reducing sugars, microcrystallinecellulose, calcium sulphate, or calcium hydrogen phosphate); lubricants(e.g., magnesium stearate, talc, or silica, steric acid, sodium stearylfumarate, glyceryl behenate, calcium stearate, and the like);disintegrants (e.g., potato starch or sodium starch glycolate); orwetting agents (e.g., sodium lauryl sulphate), colouring and flavouringagents, gelatine, sweeteners, natural and synthetic gums (such asacacia, tragacanth or alginates), buffer salts, carboxymethylcellulose,polyethyleneglycol, waxes, inert carriers (e.g., ethanol, glycerol,water), suspending agents (e.g., sorbitol syrup, cellulose derivativesor hydrogenated edible fats), emulsifying agents (e.g., lecithin oracacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethylalcohol or fractionated vegetable oils), preservatives (e.g., methyl orpropyl-p-hydroxybenzoates or sorbic acid), and the like. For otherexamples see “Remington's Pharmaceutical Sciences” by E. W. Martin, 18thEdition.

The term “subject” as used herein refers to a mammal (e.g., rodent suchas mouse or rat). In particular, the term refers to humans.

The active agents of the present invention may be administered orally,topically, parenterally, or mucosally (e.g., buccally or rectally) indosage unit formulations containing conventional non-toxicpharmaceutically acceptable carriers. It is usually desirable to use theoral route. The active agents may be administered orally in the form ofa capsule or a tablet (see Remington's Pharmaceutical Sciences, Mack 5Publishing Co., Easton, Pa.). The orally administered medicaments may beadministered in the form of a modified release formulation or device,including diffusion-controlled systems, osmotic devices,dissolution-controlled matrices, and erodible/degradable matrices.

For oral administration in the form of a tablet or capsule, the activedrug component can be combined with a non-toxic, pharmaceuticallyacceptable excipients such as binding agents, fillers, lubricants,disintegrants, colouring and flavouring agents, gelatine, sweeteners,natural and synthetic gums, buffer salts, carboxymethylcellulose,polyethyl-eneglycol and waxes.

Due to the fact that proton pump inhibitors are sensitive to pHenvironment, they need to be administered in a form protecting them fromdegradation in the stomach to allow them pass into the small intestine,the site of their absorption. On the contrary, Itriglumide does not needsuch protection.

For oral administration in liquid form, the drug components can becombined with non-toxic, pharmaceutically acceptable inert carriers,suspending agents, emulsifying agents, non-aqueous vehicles andpreservatives. Stabilising agents such as antioxidants (e.g., BHA, BHT,propyl gallate, sodium ascorbate, and citric acid) can also be added tostabilise the dosage forms.

For liquid preparations the oral administration can take the form of,for example, solutions, syrups, emulsions or suspensions, or they can bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Preparations for oral administration can besuitably formulated to give controlled or postponed release of theactive compound.

The active drugs can also be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, such as cholesterol, stearylamine orphosphatidylcholines, as is well known.

Active drugs may also be coupled with soluble polymers as targetabledrug carriers. Such polymers can include polyvinyl-pyrrolidone, pyrancopolymer, polyhydroxy-propyl methacrylamide-phenol,polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues.

Furthermore, active drug may be coupled to a class of biodegradablepolymers useful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid,polyorthoesters, polyacetals, polyhydropyrans, polycyanoacrylates, andcross-linked or amphipathic block copolymers of hydrogels.

The formulations of the invention can be delivered parenterally, i.e.,by intravenous (i.v.), subcutaneous (s.c.), intramuscular (i.m.),sub-dermal (s.d.), or intradermal (i.d.) administration, by directinjection, via, for example, bolus injection or continuous infusion.Formulations for injection can be presented in unit dosage form, e.g.,in ampoules or in multi-dose containers, with an added preservative. Thecompositions can take such forms as excipients, suspensions, solutions,or emulsions in oily or aqueous vehicles, and can contain formulatoryagents such as suspending, stabilising and/or dispersing agents.Alternatively, the active ingredient can be in powder form forreconstitution with a suitable vehicle, e.g., sterile pyrogen-freewater, before use.

Compositions of the present invention can also be formulated for rectaladministration, e.g., as suppositories or retention enemas (e.g.,containing conventional suppository bases such as cocoa butter or otherglycerides).

As disclosed herein, a proton pump inhibitor and the CCK-2 receptorantagonist Itriglumide can be mixed with excipients which arepharmaceutically acceptable and compatible with the active ingredients.In addition, if desired, the preparations may also include minor amountsof auxiliary substances such as wetting or emulsifying agents, pHbuffering agents, and/or agents that enhance the effectiveness of thepharmaceutical composition.

Although the active agents of the present invention may be administeredin divided doses, for example, two or three times daily, a single dailydose of each is preferred, with a single daily dose of both agents inone composition or in two separate compositions administeredsimultaneously being most preferred.

The instant invention also encompasses a process for preparingpharmaceutical compositions comprising combining the CCK-2 receptorantagonist Itriglumide and a proton pump inhibitor with apharmaceutically acceptable carrier and/or excipient.

Preferred specific amounts of the proton pump inhibitor which may beused in unit dosage amounts of the invention include, for example, 10 to40 mg for the PPI. Preferred specific amounts of Itriglumide which maybe used in unit dosage amounts of the invention include, for example,100 mg-600 mg.

The invention also provides a pharmaceutical pack or kit comprising oneor more containers containing one or more of the ingredients of theformulations of the invention. In a related embodiment, the presentinvention provides a kit for the preparation of the pharmaceuticalcompositions of the invention, said kit comprising the CCK-2 receptorantagonist Itriglumide in a first container, and a proton pump inhibitorin a second container, and, optionally, instructions for admixing thetwo drugs and/or for administration of the compositions. Each containerof the kit may also optionally include one or more physiologicallyacceptable carriers and/or excipients and/or auxiliary substances.Associated with such container(s) can be a notice in the form prescribedby a governmental agency regulating the manufacture, use or sale ofpharmaceuticals or biological products, which notice reflects approvalby the agency of manufacture, use or sale for human administration.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack may, for example, comprise metal or plasticfoil, such as a blister pack. The pack or dispenser device may beaccompanied by instructions for administration. Compositions of theinvention formulated in a compatible pharmaceutical carrier may also beprepared, placed in an appropriate container, and labelled for treatmentof an indicated condition.

The compositions of the invention may be administered in a modifiedrelease formulation. Modified release dosage forms provide a means forimproving patient compliance and for ensuring effective and safe therapyby reducing the incidence of adverse drug reactions. Compared toimmediate release dosage forms, modified release dosage forms can beused to prolong pharmacologic action after administration, and to reducevariability in the plasma concentration of a drug throughout the dosageinterval, thereby eliminating or reducing sharp peaks.

The majority of modified release dosage forms comprise a core eithercoated with or containing a drug. The core is then coated with a releasemodifying polymer within which the drug is dispersed. The releasemodifying polymer disintegrates gradually, releasing the drug over time.Thus, the outer-most layer of the composition effectively slows down andthereby regulates the diffusion of the drug across the coating layerwhen the composition is exposed to an aqueous environment, i.e. thegastrointestinal tract. The net rate of diffusion of the drug is mainlydependent on the ability of the gastric fluid to penetrate the coatinglayer or matrix and on the solubility of the drug itself.

According to the methods of the present invention, the pharmaceuticalcompositions described herein are administered to a patient attherapeutically effective doses, preferably, with minimal toxicity.Preferably, the proton pump inhibitor and the CCK-2 receptor antagonistItriglumide are each used at a dosage which, when combined, provide anenhanced effect, most preferably, an effect not observed uponadministration of each agent alone.

The efficacy of Itriglumide, PPI and their combination was determined inpreclinical studies using small animal models (e.g., rats) in which boththe Itriglumide and proton pump inhibitor have been found to betherapeutically effective and in which these drugs can be administeredby the same route proposed for the human clinical trials.

For any pharmaceutical composition used according to the invention, thetherapeutically effective dose can be estimated initially from animalmodels to achieve a circulating plasma concentration range that includesthe IC50 (i.e., the concentration of the test compound which achieves ahalf-maximal inhibition). Dose-response curves derived from animalsystems are then used to determine testing doses for the initialclinical studies in humans. In safety determinations for eachcomposition, the dose and frequency of administration should meet orexceed those anticipated for use in the clinical trial.

As disclosed herein, the dose of the CCK-2 receptor antagonistItriglumide in the compositions of the present invention is determinedto ensure that the dose administered continuously or intermittently willnot exceed an amount determined after consideration of the results intest animals and the individual conditions of a patient. A specific dosenaturally varies (and is ultimately decided according to the judgment ofthe practitioner and each patient's circumstances) depending on thedosage procedure, the conditions of a patient or a subject animal suchas age, body weight, sex, sensitivity, feed, dosage period, drugs usedin combination, seriousness of the disease, etc. As disclosed herein, anappropriate dose of a Itriglumide is generally in the range of 2 to 10mg per kg of the body weight/day.

Toxicity and therapeutic efficacy of the compositions of the inventioncan be determined by standard pharmaceutical procedures in experimentalanimals, e.g., by determining the LD50 (the dose lethal to 50% of thepopulation) and the ED50 (the dose therapeutically effective in 50% ofthe population). The dose ratio between therapeutic and toxic effects isthe therapeutic index and it can be expressed as the ratio ED50/LD50.Compositions that exhibit large therapeutic indices are preferred.

The data obtained from animal studies can be used in formulating a rangeof doses for use in humans. The doses of derivatives used in humans arepreferably within a range of circulating concentrations that include theED50 with little or no toxicity. The dosage can vary within this rangedepending upon the dosage form employed and the route of administrationutilised.

The drug combination of the invention is not only highly effective atrelatively low doses but also possesses low toxicity and produces fewside effects.

Preclinical Studies

The combination treatment of Itriglumide with omeprazole, taken as therepresentative of PPIs, has been studied in comparison with themonotherapy of the same drugs in two models of acute and chronicesophagitis in rats, mimicking human reflux esophagitis conditions.

Effect on Acute Reflux Esophagitis in Rats

Male rats of 175-200 g body weight were fasted for 24 hours prior theexperiment. Water was allowed ad libitum. Under ether anaesthesia, theabdomen was incised along the midline, and both pylorus and limitingridge (transitional region between the forestomach and corpus) weresimultaneously ligated. Consequently, the total capacity of the stomachto hold gastric juice was greatly diminished, resulting in reflux ofgastric juice into the esophagus. Following ligation of pylorus andlimiting ridge, the test compounds were given intraduodenally (5 ml/kg),and the abdomen was closed by suturing. After 3 hours, rats were killedby ether overdose and the gastroesophageal portion was excised. Thelesion in the thoracic esophagus was scored macroscopically, using alesion index according to the following criteria: no lesion as 0; oedemaas 1; reddening as 2; the length of hemorrhagic area <20 mm as 3; thelength of hemorrhagic area 20-30 mm as 4; the length of hemorrhagic area30-40 mm as 5; the length of hemorrhagic area >40 mm or perforation as6.

The doses of the tested compounds which reduce of 50% the esophaguslesions (ED₅₀) were calculated from the dose-response regression line.

The results thus obtained are given in Table 1.

TABLE 1 Protective effects of Itriglumide, omeprazole and theircombination treatment on acute reflux esophagitis in pylorus-ligatedrats Average % Effect Treatment Doses Score vs. Group (mg/kg) lesionscontrol ED₅₀ Control Saline 5.1 — — Itriglumide 2.5 5.2 0 5.0 3.7 27.59.1 mg/kg 10 2.5 51.0 20 0.9 82.3 Control Saline 5.8 — — Omeprazole 0.15.6 3.4 0.3 5.8 0 4.9 mg/kg 1.0 4.8 17.2 3.0 2.7 53.4 Control Saline 5.6— Itriglumide + Omeprazole 2.5 + 0.3 4.8 14.3 (Itriglumde + 0.3 mg/kg ″2.5 + 1.0 4.0 28.6 Omeprazole) = 5.3 mg/kg ″ 5.0 + 0.3 2.5 55.4 ″ 5.0 +1.0 1.4 75.0 ″  10 + 0.3 1.5 73.2 (Itriglumide + 1.0 mg/kg  10 + 1.0 0.394.6 Omeprazole) = 3.6 mg/kg

The calculated protective effects of Itriglumide and Omeprazoleadministered separately were 9.1 mg/kg and 4.9 mg/kg, respectively.

The combination treatment of two compounds produced an increase in theprotective effect. The calculated ED50 for the combination treatmentwere 5.3 mg/kg for Itriglumide plus Omeprazole (0.3 mg/kg) and 3.6 mg/kgfor Itriglumide plus Omeprazole (1 mg/kg), respectively.

In average the combination treatment produced a synergistic increasingefficacy for both examined drugs. For example, as disclosed herein, thecombination treatment of 5 mg/kg Itriglumide plus 1 mg/kg Omeprazoleproduced an 75% protective effect versus a 45% expected, this latterbeing the sum of the results obtained with the equivalent separate drugtreatment, i.e. 27.5 and 17.2% of protective effect, respectively.

Effect on Chronic Acid Reflux Esophagitis in Rat

The method was according to Omura N., et al. (Scand. J gastroenterol.1999; 34:948-953) with slight modifications.

Male Wistar rats, 10 weeks old, were kept in controlled animal room 1week prior to use and fed with standard diet. A day before theexperiment rats were deprived of food but allowed free access to water.

Surgery

This model consists of gastric outlet obstruction obtained by ligationof forestomach and pyloric stenosis. Rats were operated underair/halothane anaesthesia; after opening the abdomen with a medianincision, the transitional region between forestomach and the glandularportion was ligated and then the forestomach was blocked with other twoligations. Pyloric stenosis were obtained by wrapping a duodenum nearthe pylorus with a piece (about 2 mm) of a catheter (3.5 mm innerdiameter) as a ring. The ring was closed by thermocautery and fixed tothe pylorus with a nylon thread. The abdomen was closed by suturing.

After the operation the rats (10 animals per group) were deprived ofdiet for 48 h but had free access to water.

Drug Efficacy

Drugs were administered once a day, starting on day zero, bysubcutaneous injection. During the experiment body weight as well as themortality were recorded.

The animals were killed 15 days later by overdose of ether inhalation.The abdomen was opened and the esophagus excised and placed on a corkplate. The presence and extension of esophagitis sites was evaluated bymacroscopic observation. Each site of esophagitis was measured (mm oflength×mm of width). Data were expressed as mm² of esophagitis area(mean area group). The results are shown in Table 2.

TABLE 2 Protective effects of itriglumide, omeprazole and theircombination treatment on a chronic model of reflux esophagitis in ratsTotal average % Protection Treatment Doses Survival Occurrence size ofulcers vs. ED₅₀ Group (mg/kg) Rate (%) of Esophagitis (mm²) control(mg/kg) Control — 80 8/8 57 — — Itriglumide 10 90 4/9 33 42.1 —Omeprazole 0.5 80 6/8 47 17.5 2.2 ″ 1 90 6/9 41 28.0 ″ 2 90 3/9 29 49.1Itriglumide 0.5 90 2/9 16 71.9 0.16 (10 mg/kg) + Omeprazole Itriglumide1 100  1/10 6 89.5 (10 mg/kg) + Omeprazole Itriglumide 2 100  0/10 0 100(10 mg/kg) + Omeprazole

The combination treatment of Itriglumide with a PPI may offer manyadvantages.

Itriglumide has a rapid onset of action by blocking the gastrin receptorand reducing acid secretion. On the contrary, PPIs are metabolised inthe gastric parietal cells to give the active sulphenimide metabolitesthat inactivate the sulphydryl group of the proton pump, thus blockingthe hydrogen-ion secretion. This process requires some time and PPIs maytake up to 3-5 days to achieve maximal efficacy in inhibiting gastricacid secretion and 5 to 8 days to induce a complete a sustainedresolution of heartburn (Richter J E et al. 2001: 96: 656-665).

Therefore, by combining Itriglumide with PPIs, it is possible to obtainrapid onset of action, as well as good long-term efficacy. Furthermore,the gastric pH increasing effect produced by Itriglumide may increasethe absorption of the acid-labile PPIs, allowing the drugs to reach theupper small intestinal region in an intact, absorbable unionised form.This speculation may explain the synergic effect exhibited by thecombination treatment in both acute and chronic esophagitis experimentsshown previously.

In fact, the results shown in Tables 1 and 2 demonstrate that theOmeprazole-Itriglumide combination treatment may allow to stronglyreduce the Omeprazole dosage, maintaining at the same time the sameefficacy. This effect and the concomitant blocking activity ofItriglumide on gastrin receptor may offer the possibility to reduce therisk, especially during long-term therapy, of hyperplasia of theECL-cells in the gastric mucosa, induced by the increase in the serumgastrin due to a long-lasting achlorhydria situation. In addition ifgastrin via activation of CCK-2 receptors is implicated in thepathogenesis of dyspeptic symptoms, the combination of Itriglumide andPPIs might offer the additional advantage of providing a completesymptom relief.

It should be understood that the invention is not limited to theparticular embodiments described herein, but that various changes andmodifications may be made without departing from the spirit and scope ofthis novel concept as defined by the following claims.

1. A method for relieving or alleviating symptoms of gastroesophagealreflux disease by administering a medicament comprising: (i) aCCK-2/gastrin antagonist itriglumide, or its racemate or apharmaceutically acceptable salt thereof and (ii) an ATP-ase proton pumpinhibitor selected from the group consisting of omeprazole,esomeprazole, lansoprazole, pantoprazole, rabeprazole, andpharmaceutically acceptable salts thereof, in an amount sufficient torelieve or alleviate symptoms of gastroesophageal reflux disease.
 2. Amethod according to claim 1, wherein said medicament comprises (i)itriglumide or its racemate, and (ii) a proton pump inhibitor in a formsuitable for conjoint administration.
 3. A method according to claim 1,wherein the proton pump inhibitor is omeprazole.
 4. The method accordingto claim 1, wherein said amount sufficient results in an increasedefficacy for treating said gastrointestinal disorders greater than theadded efficacy of (i) or (ii).
 5. A method for relieving or alleviatingsymptoms of gastroesophageal reflux disease by administering asynergistic combination of compounds which comprise: (i) a CCK-2/gastrinantagonist itriglumide, or its racemate or a pharmaceutically acceptablesalt thereof and (ii) an ATP-ase proton pump inhibitor selected from thegroup consisting of omeprazole, esomeprazole, lansoprazole,pantoprazole, rabeprazole, and pharmaceutically acceptable saltsthereof, in a synergistically therapeutic amount sufficient to relieveor alleviate symptoms of gastroesophageal reflux disease.